The broad aim of this 5 year research study is to advance understanding of the neurophysiological and biological bases of schizophrenia. The first project proposed is a study of first episode psychotic patients and matched normal controls. The major questions to be addressed are whether the event-related potential (ERP) abnormalities we have found to characterize chronic schizophrenics are present at first hospitalization, without the confounds associated with chronicity. The major ERP paradigm will be the auditory oddball P300, on which chronic schizophrenics have shown both an overall amplitude reduction and a topographic abnormality, a left temporal scalp region amplitude reduction (left temporal feature, LTF). We predict these abnormalities will be present at the first episode and will differentiate those patients diagnosed as schizophrenic on retest one year later vs. those with mood disorder or transient psychosis. The importance of such potential diagnostic predictors is evident. Other ERPs elicited in the oddball paradigm will also be studied (Nl00, P200, N200), as will the N400. These ERPs provide additional indices of information processing abnormalities and thus the determination of their time of onset and prognostic value is also important. The second major project involves correlation of ERP abnormalities in chronic schizophrenics with quantitative volumetric Magnetic Resonance Imaging (MRI) definition of specific regions of interest (ROI) in temporal and frontal lobe. This approach combines the strengths of a technology with high time resolution and functional information (ERPs) with one having a high spatial resolution (MRI). This project takes advantage of the advanced imaging capabilities of the Brigham and Womens Hospital MRI facility. It predicts quite specific sets of correlations between abnormalities in ERPs and clinical features, and of volume reduction in specific MRI ROI in schizophrenics, whereas matched normals are expected to show no MRI-ERP correlations. The paradigmatic prediction is an association between the P300 LTF/clinical thought disorder and volume, reduction of the left posterior superior temporal gyrus (STG) gray matter in right-handed subjects. Our working hypothesis is that part of the pathophysiology of schizophrenic thought is explained by 2 disturbance in the language/auditory -related cortical areas, and that the P300 amplitude reduction reflects a disturbance of memory updating that is dependent on the same brain regions. In left handed subjects we predict the P300 amplitude reduction in the right temporal scalp region will correlate with reduced volume in the right posterior STG; this association with hand dominance may reflect abnormalities associated with schizophrenic hemispheric specialization. Other ERP-MRI associations may also provide clues as to which abnormal brain regions are responsible for abnormalities of information processing. Other components of the research program will examine the association of ERP- and MRI-defined biological abnormalities with neuropsychological/cognitive probes that complement the ERP probes. It is predicted that disturbances of semantic memory and association will be related to hippocampal-auditory association cortex while disturbances of attention apparent in the Posner and computer-controlled Continuous Performance Task will be associated with prefrontal cortex abnormalities, especially on the left (in right-handed subjects) and especially in middle and inferior frontal gyri gray matter.